The retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) and type-2 (HIV-2) viruses, have been etiologically linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. Replication of HIV by a host cell requires integration of the viral genome into the host cell's DNA. Since HIV is a retrovirus, the HIV replication cycle requires transcription of the viral RNA genome into DNA via an enzyme known as reverse transcriptase (RT).
Reverse transcriptase has three known enzymatic functions: The enzyme acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. In its role as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. As a ribonuclease, RT destroys the original viral RNA and frees the DNA just produced from the original RNA. And as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by the integrase enzyme.
It is known that compounds that inhibit enzymatic functions of HIV RT will inhibit HIV replication in infected cells. These compounds are useful in the prophylaxis or treatment of HIV infection in humans. Among the compounds approved for use in treating HIV infection and AIDS are the RT inhibitors 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC), d4T, 3TC, nevirapine, delavirdine, efavirenz and abacavir.
While each of the foregoing drugs is effective in treating HIV infection and AIDS, there remains a need to develop additional HIV antiviral drugs including additional RT inhibitors. A particular problem is the development of mutant HIV strains that are resistant to the known inhibitors. The use of RT inhibitors to treat AIDS often leads to viruses that are less sensitive to the inhibitors. This resistance is typically the result of mutations that occur in the reverse transcriptase segment of the pol gene. The continued use of antiviral compounds to prevent HIV infection will inevitably result in the emergence of new resistant strains of HIV. Accordingly, there is a particular need for new RT inhibitors that are effective against mutant HIV strains.
The following references are of interest as background:
WO 02/070470 (corresponding to US 2004/0122064) describes benzophenones as inhibitors of reverse transcriptase.
WO 2003/029184 (corresponding to US 2004/0242654) describes diaryl ether derivatives as immunosuppressants.
WO 96/37204 (corresponding to U.S. Pat. No. 5,710,171) describes 3-substituted phenoxy compounds as farnesyl-protein transferase inhibitors.
U.S. Pat. No. 3,600,437 discloses certain phenylalkanoic acid derivatives including certain phenoxyphenylalkanamides, phenylthiophenylalkanamides, and certain tetrazoles. The compounds are disclosed to be useful as antiinflammatory, analgesic and antipyretic agents.
U.S. Pat. No. 5,665,737 discloses certain cycloalkyloxyphenylalkylbenzoxazole compounds including 7-bromo-5-chloro-2-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]ethyl]benzoxazole. The compounds are disclosed to be effective in the mediation or inhibition of PDE IV.
U.S. Pat. No. 5,994,376 discloses certain cycloalkyloxyphenylalkyl-2H-imidazolone compounds including 1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]ethyl]-1,3-dihydro-2H-imidazol-2-one. The compounds are disclosed as useful for treating disease states related to abnormal enzymic or catalytic activity of PDE IV.
U.S. Pat. No. 6,057,346 discloses the inhibition of retroviral LTR promoters by a class of calcium response modifiers that includes certain imidazolylalkyl- and triazolylalkyl-substituted diaryl compounds in which the aryl moieties are linked by O, S, SO2, or another linking group.
U.S. Pat. No. 6,348,032 B1 discloses inhibition of neoplastic cells with a genus of certain benzimidzole derivatives including certain (phenyloxyphenyl)alkylbenzimidazoles.
Other references disclosing linked diaryl compounds of interest include EP 622077 A1; US 2005/0095215 A1; and Feit et al., J. Med. Chem. 1972, 15: 79-83.
The compounds described in this invention represent a novel structural class of non-nucleoside reverse transcriptase inhibitors.